1-alkyl-2 or 4-[(n-alkyl-n-beta-dialkyl-aminoalkyl) aminophenethyl]-piperidines and salts thereof



Patented Jan. 27, 1953 UNITED STATES Mrs-NT OFFICE L lALKYL-Z OR? 4-'[(N-ALKYL-N-fl-DIALKYL- ..AMINOALKYL) 1, AMINOBHENETHYL] PI- .PERIDINES ,AND SALTS. THEREOF Jacob Finkelstein, East Paterson,- and' John Lee, Essex Fells;-N.' J., assignorstdH'offmann-La Roche-Inc.',Nutley, N. .L; a icorporation cit-New Jersey No Drawing. ApplicationJuly124,'1950,

. Serial No. l75,655

. 12Claims. (Cl. 260-293) This-inventionrelates to new chemical compounds, which .can be described broadlyasxcertain substituted .piperidine bases and their acid I 4-position thereof, the piperidine beingotherwise unsubstituted. The alkyl groups can. be the same or different. The-following-compounds:can be instanced as illustrative'of these piperidines: lmethyl-2-[4-(N methyl N a e diethylaminoethyl) -aminophenethyll -piperidine, l-n-hexyl-2- [4 (N methyl-N-B-diethylaminoethyl)aminophenethyl] piperidine, 1-methy1-4-[4-(N-methyl-N-B-diethylaminoethyl) aminophenethyl] epiperidine, and 1-ethyl-4- [4-5(Nemethyl N fl-diethyl aminoethyl),aminophenethyl] piperidine. ..The compounds of the invention can be represented by the following general FormulaeliI). and. (II),

.in whichR R RitandRt each ..representsan alkyl group and Rirepresents an .alkylenegroup:

@v A g CHZOEHQ in (I) i The salts of the invention-are the acid addition salts of the above piperidines-with inorganic and organic acids, ands-particularly with "non-toxic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, and tartaric acids, and the like.

The piperidine bases can be prepared by a process comprising :reacting an alkyl halide quaternarysalt of amethyl-substituted pyridine- (es g. -v.-.-.picoline-tmethiodide'ror -y=pico1ine ethiodide) 2 dialkylaminoalkylliaminopyridinium salt, and catalytically 'reducing the latter to form 'an acidtaddition'salt of al-alky1- 2 (or 4) (N-alkyl-N -p-dialkylaminoalliyl) amino- 'phenethy1]-piperidine. The free 1-alkyl-2(or"4) [(N-alkyl-N-5-dialkylaminoalkyl) aminophenethyll-pi-peridine base can be liberated-from'the latter saltby alkalinization, and 'can'thenbej'converted to any desired acid additionsalt: by treatment' with the appropriate acid.

' The invention isfurther 'discloseddnthefollowing examples, which are illustrative'fbutznotlimitative thereof.

EXAMPLE '1 l-methyl-Z-[4-(Nr-methyleN {3 dieting laminaethyl) aminophenethyl] -piperidine A mixture of .1000 g. of N-methylaniline, 1073 g. of B-diethylaminoethyl chloride hydrochloride, 800 ccrof ethanol and 850 g.- of crystalline sodium acetate was refluxed for 8 hours'while stirring.

Then the reaction mixture was cooled'and water was added thereto, resultingin separation into an aqueous phase and an oily-phase. 'The' oily phasewas extracted with ether, the-ether extract was dried over potassiumcarbonate'andi'therr was concentrated by removal of the-solvent. The residue was distilled .underreducedpressurepand .the' fraction boiling at 1'10-115 C.1:at-2--mm.

Hg wascollected. This product was 'N m'ethyl- N-Bediethylaminoethyl aniline.

jrIn a 3-neck" flask equippedi'with stirrer;::condenser, thermometer, and dropping funnelg were placed cc. of dry benzene; and g. (of 'N- methylformanilide wereadded thereto. While stirring and cooling to keep the temperature between 5 and '15" 'C.,153.5 g. of phosphorus oxycholride were added, dropwise. The reaction'mixture was stirred at room temperature for about 2 hours. Then the mixture was cooled to 5-15 "C., and 109 g. of N.-methyl-NB-diethylaminoethyl-aniline were added slowly while stirring. The mixture became very viscous and in order to make it more fluid, it was warmed ,to.60-170f C., then it was stirred at that temperature for. 2 hours. At the end of this time, it was poured onto ice and allowed tostand for approximately 60 hours. Then it was made alkaline with. 30 per cent NaOI-I, and the oil which was liberated was extracted with benzene. The benzene was removed from the extract, and the' residual oil was fractionated runder v-reducedvpressure. T The scribed lunder 200 lbs. hydrogen pressure.

fraction boiling at 165-177 C. at 1 mm. Hg was p-(N-methyl N B diethylaminoethyl) aminobenzaldehyde.

9.3 g. of a-picoline was mixed with 14.2 g. of methyl iodide and allowed to react spontaneously. The resulting white solid, 1,2-dimethyl-pyridinium iodid (a-picoline methiodide) was washed with alcohol, to remove unreacted starting materials.

A mixture of 11.8 g. of 1,2-dimethyl-pyridinium iodide, 11.7 g. of p-(N-methyl-N-p-diethylaminoethyDaminobenzaldehyde, 20 cc. of ethanol, and 0.5 cc. of piperidine was refluxed for 21 hours. The reaction mixture was cooled and the precipitate was filtered oif and recrystallized from alcohol. The product obtained was l-methyl- 2 [4 (N methyl N 3 diethylaminoethyl) styryll-pyridinium iodide, M. P. approximately 164-165 C.

45 g. of the latter product suspended in 300 cc. of 95 per cent alcohol was catalytically reduced in the presence of 0.2 g. of platinum dioxide at 50 C. and under 200 lbs. hydrogen pressure. The reaction mixture was filtered to remove the catalyst. and to the resulting filtrate was added excess dilute sodium hydroxide. The oil which separated was extracted with ether. The extract was washed with water, dried over potassium carbonate, and the solvent removed therefrom. The

.residual oil was concentrated under reduced pressure. The fraction having a B. P. of approximately 193 C. at 0.5 mm. Hg was l-methyl- 2- [4 (N methyl-N-p-diethylaminoethyl) aminophenethyl] -piperidine.

The trihydrochloride of the latter product was prepared by reacting 15 g. of the free base with 136 cc. of IN 1101.

EXAMPLE 2 I-ethyl-Z- [4- (N -methyl-N -fi-dz'ethylaminoethyl) aminophenethyl] -piperidine dinium iodide, 34 g. of p-(N-methyl-N-B-diethylaminoethyl)aminoloenzaldehyde, 75 cc. of ethan01, and 5 cc. of piperidine was refluxed for 4 hours. The product, isolated in the manner dein Example 1, was 1-ethyl-2-[4-N- methyl N B diethylaminoethyl) aminostyryllpyridinium iodide.

116 g. of the latter product in 1100 cc. of 95 per cent alcohol was catalytically reduced in the presence of 0.3 g. of platinum dioxide at 50 C. and The reaction mixture was worked up in the manner described in Example 1. The product, having a B. P. of approximately 193-205 C. at 1 mm. Hg, was 1-ethyl-2- [4-N methyl N B diethylaminoethyl) aminophenethyl] -piperidine.

The trihydrochloride of the latter product was prepared by reacting 9.94 g. of the free base with 86.33 cc. of 1N HCl.

EXAMPLE 3 1 -n-hea:yl-2- [4 N -methyl-N -fl-diethylaminoethyl) aminophenethyl piperidine 93 g. of a-picoline was mixed with 165 g. of

n,-hexy1 bromide and heated at 135-140 C. for- 24 hours. After standing for an hour, the reaction mixture was extracted alternately with ether and petroleum ether several times. The extracts were discarded and the insoluble oil was allowed to stand at 0 C. for about 15 hours to crystallize. The resulting crystalline material was filtered off and washed with ether and petroleum ether. It was 1-n-hexyl-2-methyl-pyridinium bromide(a-picoline n-hexyl bromide).

A mixture of 59 g. of 1-n-hexy1-2-methyl-pyridinium bromide, 56 g. of p-(N-methyl-N-B-diethylaminoethyl)aminobenzaldehyde, cc. of ethanol and 10 cc. of piperidine was refluxed for 20 hours. The reaction mixture was concentrated by distilling oil as much of the alcohol as possible. The residue was allowed to stand at 0 C. for 3 days, and the crystalline precipitate was filtered off. After recrystallization from isopropanol, the product melted at approximately 194- 197 C. It was 1-n-hexyl-2-[4-(N-methyl-N-fidiethylaminoethyl) aminostyryl] -pyridinium bromide.

118.5 g. of the latter product in 1100 cc. of 95 per cent alcohol was catalytically reduced in the presence of platinum dioxide at 50 C. and under 200 lbs. hydrogen pressure. The product was isolated in the manner described in Example 1. It was l-n-hexyl-Z- [4- (N-methyl-N-[i-diethylaminoethyl)aminophenethyl]-piperidine, B. P. approximately 225 C. at 1 mm. Hg.

The trihydrochloride of the latter product was prepared by reacting 20 g. of the base with approximately cc. of 1N HCl.

EXAMPLE 4 1 -methyZ-4- [4- (N -methyl-N -fl-diethylaminoethyl) aminophenethyl] -piperidine 1,4 dimethyl pyridinium iodide ('y picoline methiodide) was prepared by reacting 93 g. of -picoline with 14.2 g. of methyl iodide. A mixture of 11.8 g. of 1,4-dimethyl-pyridinium iodide, 11.7 g. of p-(N-methyl-N-p-diethylaminoethyl-aminobenzaldehyde, 20 cc. of ethanol and 0.5 cc. of piperidine was refluxed for 21 hours. The crystalline product recovered from the reaction mixture was 1-methyl-4-[4-(N-methyl-N-fl-diethylaminoethyl) aminostyryl] -pyridinium iodide, M. P. approximately -172 C.

46.5 g. of the latter product in 250 cc. of 95 per cent alcohol was catalytically reduced in the presence of platinum dioxide at 50 C. under 200 lbs. hydrogen pressure. The reaction mixture was worked up in the manner described in Example 1. The product, 1-methyl-4-l4-(N-methyl N 6 diethylaminoethyl)aminophenethyllpiperidine, had a B. P. of approximately 192- 198 C. at 0.5 mm. Hg.

The dihydrochloride of the latter base was prepared by reacting 12.3 g. of the free base with 74.2 cc. of 1N HCl.

EXANIPLE5 1 ethyl 4 [4 (N methyl N p diethylaminoethyl)aminophenethyl] piperidine 93 g. of 'y-picoline were mixed with 156 g. of ethyl iodide in benzene and refluxed. After 2 hours,- the reaction mixture was cooled. The precipitated product, 1 ethyl 4 methyl-pyridilnium iodidecy-picoline ethiodide) was filtered o A mixture of 12.5 g. of 1-ethyl-4-methylpyridinium iodide, 11.7 g. of p-(N-methyl-N-pdiethylaminoethyl)aminobenzaldehyde, 15 cc. of ethanol, and 1 cc. of piperidine was refluxed for 18 hours. The product was 1-ethy1-4-[4-(N 5 methyl N B diethylaminoethyl) aminostyryllpyridinium iodide.

52.? g. of the latter product in 250 cc. of 95 per cent alcohol was catalytically reduced in the presence of platinum dioxide at 42 C. and under 250 lbs. hydrogen pressure. The reaction mixture was worked up in the manner described in Example 1. The product, B. P. approximately 200-204 C. at 0.5 mm. Hg, was 1-ethy1-4-[4- (N methyl N p diethylaminoethyl)aminophenethyl] -piperidine.

The dihydrochloride of the latter compound was prepared by reacting 12.38 g. of the free base with 71.70 cc. of 1 N HCl.

EXANIPLEG 1 -n-hexyZ-4- [4- (N-methyZ-N-B-diethylaminoethyl) aminophenethyl] -piperidine 1 n hexyl 4 methyl pyridinium bromide ('y-picoline-n-hexyl bromide) was prepared by heating 93 g. of -picoline with 139 g. of nhexyl bromide at 135-140 C. for 24 hours. After cooling the reaction mixture, the unreacted starting materials were removed from the crystalline product by extraction with dry ether.

A mixture of 129 g. of 1-n-hexyl-4-methylpyridinium bromide, 117 g. of p-(N-methyl-N- p-diethylaminoethyl)aminobenzaldehyde, 250 cc. of alcohol, and 15 cc. of piperidine was refluxed for 16 hours. The crystalline product recovered from the reaction mixture was 1-n-hexyl-4-[4- (N methyl N 8 diethylaminoethyDaminostyryllpyridinium bromide.

40.7 g. of the latter compound in 250 cc. of 95 per cent alcohol was catalytically reduced in the presence of platinum dioxide at 50 C. and under 200 lbs. hydrogen pressure. The product was isolated in the manner described in Example 1. It was 1-n-hexyl-4-[4-(N-methyl-N- ,3 diethylaminoethyl) aminophenethyl] piperidine B. P. approximately 219 C. at 0.1 mm. Hg.

The dihydrochloride of the latter compound was prepared by reacting 8.46 g. of the free base with 42.13 cc. of 1 N HCl.

We claim:

1.1-ethyl-2- [4-(N-methyl-N-fldiethylaminoethyl) aminophenethyll piperidine.

2.1 -n-hexy1-2- [4- (N-methyl-N-fidiethylaminoethyl) aminophenethly] piperidine.

6 3.1-methyl-4-[4-(N-methyl-N-fi-diethylaminoethyl)aminophenethyl] piperidine.

4. A compound selected from the group consisting of 1 alkyl 2 [(N alkyl N B dialkylaminoalkyl)aminophenethyl] piperidines, 1 alkyl 4 [(N alkyl N [3 dialkylaminoalkyl)aminophenethyl] piperidines, and. acid addition salts of said piperidines; each of the alkyl groups in said compound being a lower alkyl group.

5. A1 -a1kyl-2- [4- (N-alkyl-N-B-dialkylaminoalkyl)aminophenethyl] piperidine, each of the alkyl groups therein being a lower alkyl group.

6. An acid addition salt of a compound accord to claim 5.

7. A1-a1ky1-4- [4- (N-alkyl-N-B-dialkylaminoalkyl)aminophenethyl] piperidine, each of the alkyl groups therein being a lower alkyl group.

8. An acid addition salt of a compound according to claim '7.

9.1 -methyl 2 [4 (N methyl N p diethylaminoethyl)aminophenethyll piperidine.

10. An acid addition salt of the compound of claim 9.

11. A hydrohalide of the compound of claim 9.

12.1 methyl 2 [4 (N methyl N p diethylaminoethyl)aminophenethyl] piperidine trihydrochloride.

JACOB FINKELSTEIN. JOHN LEE.

REFERENCES CITED The following references are of record in the file of this patent:

FOREIGN PATENTS Country Date Great Britain Dec. 11, 1947 OTHER REFERENCES Number 

4. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1 - ALKYL - 2 - (N - ALKYL - N B - DIALKYLAMINOALKYL)AMINOPHENETHYL) - PIPERIDINES, 1 - ALKYL - 4 - (N - ALKYL - N - B - DIALKYLAMINOALKYL)AMINOPHENETHYL) - PIPERIDINES, AND ACID ADDITION SALTS OF SAID PIPERIDINES; EACH OF THE ALKYL GROUPS IN SAID COMPOUND BEING A LOWER ALKYL GROUP. 